Avian-human influenza A reassortant viruses containing human influenza hemagglutinin and neuraminidase genes and the six internal genes of either the avian influenza A/Mallard/78 (H2N2) or A/Pintail/79 (H4N6) virus are attenuated for monkeys and humans. The NP and M genes of the avian influenza A/Mallard/78 virus are individually capable of producing attenuation. NP genes of three avian influenza A viruses were found to have significant divergence of their amino acid sequences from those of three human influenza A viruses. Unlike the M gene of avian influenza A/Mallard/78 virus, the M gene of avian influenza A/Pintail/79 virus is incapable by iself of attenuating an avian-human influenza A reassortant virus. A specific constellation of polymerase genes of the avian influenza A/Pintail/79 virus produces a host range specific restriction of viral replication in MDCK tissue culture. Studies with single gene reassortant viruses derived from the human influenza A/Ann Arbor/60 ca donor virus show that the NP and NS genes of the ca virus are individually not important in producing the attenuated ca phenotype. Single gene M, NP, and NS reassortants were not ts.